In atopic asthma, activated T helper lymphocytes are present in bronchial-biopsy specimens and bronchoalveolar-lavage (BAL) fluid, and their production of cytokines may be important in the pathogenesis of this disorder. Different patterns of cytokine release are characteristic of certain subgroups of T helper cells, termed T_H1 and T_H2, the former mediating delayed-type hypersensitivity and the latter mediating IgE synthesis and eosinophilia. The pattern of cytokine production in atopic asthma is unknown. We assessed cells obtained by BAL in subjects with mild atopic asthma and in normal control subjects for the expression of messenger RNA (mRNA) for interleukin-2, 3, 4, and 5, granulocytemacrophage colony-stimulating factor (GM-CSF), and interferon gamma by in situ hybridization with ³²P-labeled complementary RNA. Localization of mRNA to BAL T cells was assessed by simultaneous in situ hybridization and immunofluorescence and by in situ hybridization after immunomagnetic enrichment or depletion of T cells. As compared with the control subjects, the subjects with asthma had more BAL cells per 1000 cells that were positive for mRNA for interleukin-2 (P<0.05), 3 (P<0.01), 4 (P<0.001), and 5 (P<0.001) and GM-CSF (P<0.001). There was no significant difference between the two groups in the number of cells expressing mRNA for interferon gamma. In the subjects with asthma, mRNA for interleukin-4 and 5 was expressed predominantly by T lymphocytes. Atopic asthma is associated with activation in the bronchi of the interleukin-3, 4, and 5 and GM-CSF gene cluster, a pattern compatible with predominant activation of the T_H2-like T-cell population. (N Engl J Med 1992;326:298–304.)

Glucocorticoid (GC)-insensitive asthma is a challenging clinical problem that can be associated with life-threatening disease progression. The molecular basis of GC insensitivity is unknown. Alternative splicing of the GC receptor (GCR) pre-mRNA generates a second GCR, termed GCR β, which does not bind GC but antagonizes the transactivating activity of the classic GCR. Thus increased expression of GCR β could account for glucocorticoid insensitivity. Bronchoalveolar lavage (BAL) cells and peripheral blood mononuclear cells (PBMC) were examined for GCR β immunoreactivity using a GCR β -specific antibody by immunohistochemical staining. Cell localization of GCR β expression was performed using a double immunostaining technique. Patients with GC-insensitive asthma expressed a significantly higher number of GCR β -immunoreactive cells in their BAL and peripheral blood than GC-sensitive asthmatics or normal control subjects. Furthermore, GCR β expression in GC-insensitive asthma was particularly high in airway T cells, which are thought to play a major role in the pathogenesis of asthma. We also examined the expression of GCR β in specimens from the airways of patients with chronic bronchitis. In chronic bronchitis, few cells were GCR β -positive and their numbers did not differ significantly from normal control subjects. We conclude that GC-insensitive asthma is associated with increased expression of GCR β in airway T cells.

A) To evaluate in septic patients the blood levels of endocan, a circulating proteoglycan, which regulates leukocyte function-associated antigen-1/intercellular adhesion molecule-1 interactions in vitro; b) to determine whether endocan could be used as a diagnostic and prognostic marker in sepsis in the intensive care unit; and c) to study kinetics of endocan secretion by endothelial cells in vitro after stimulation by soluble mediators involved in sepsis. Prospective observational study. Intensive care unit of the University Hospitals of Lille, France, and Geneva, Switzerland. All patients admitted to the intensive care unit over a 6-month period with clinical evidence of severe sepsis or septic shock. None. In vitro, we showed a sustained endocan secretion by endothelial cells after stimulation by lipopolysaccharide and tumor necrosis factor-α. Circulating levels of endocan measured in 63 patients admitted to the intensive care unit with sepsis were significantly elevated compared with 20 healthy donors and seven patients with systemic inflammatory response syndrome: 2.71 ± 4.88 ng/mL vs. 0.77 ± 0.44 ng/mL vs. 0.68 ± 1.03 ng/mL (median ± interquartile range, p < .001). Endocan levels were higher in patients with septic shock (6.11 ± 12.99 ng/mL, n = 22) than in patients with severe sepsis (1.97 ± 7.8 ng/mL, n = 12) or sepsis (1.95 ± 1.63 ng/mL, n = 29). Measurement of endocan at intensive care unit admission revealed higher levels in nonsurvivors (n = 12) than in patients still alive 10 days later (n = 51, 6.98 ± 13.8 vs. 2.45 ± 4.09, p < .01). These results suggest that in septic patients, endocan blood level is related to the severity of illness and the outcome of the patient and may represent a novel endothelial cell dysfunction marker.

ICAMs are ligands for LFA-1, a major integrin of mononuclear cells involved in the immune and inflammatory processes. We previously showed that endothelial cell specific molecule-1 (ESM-1) is a proteoglycan secreted by endothelial cells under the control of inflammatory cytokines. Here, we demonstrate that ESM-1 binds directly to LFA-1 onto the cell surface of human blood lymphocytes, monocytes, and Jurkat cells. The binding of ESM-1 was equally dependent on Ca²⁺, Mg²⁺, or Mn²⁺ divalent ions, which are specific, saturable, and sensitive to temperature. An anti-CD11a mAb or PMA induced a transient increase in binding, peaking 5 min after activation. Direct binding of ESM-1 to LFA-1 integrin was demonstrated by specific coimmunoprecipitation by CD11a and CD18 mAbs. A cell-free system using a Biacore biosensor confirmed that ESM-1 and LFA-1 dynamically interacted in real time with high affinity (K_d = 18.7 nM). ESM-1 consistently inhibited the specific binding of soluble ICAM-1 to Jurkat cells in a dose-dependent manner. These results suggest that ESM-1 and ICAM-1 interact with LFA-1 on binding sites very close to but distinct from the I domain of CD11a. Through this mechanism, ESM-1 could be implicated in the regulation of the LFA-1/ICAM-1 pathway and may therefore influence both the recruitment of circulating lymphocytes to inflammatory sites and LFA-1-dependent leukocyte adhesion and activation.